Gastric dysmotility in calorically restricted mice is associated with depletion of ICC and enteric neurons

Background: Dyspeptic symptoms and gastric dysrhythmias commonly accompany chronic caloric insufficiency in patients with primary eating disorders and secondary protein-energy malnutritionstion. The mechanisms of gastric dysmotility remain unclear. Calorie deficit reduces IGF-I, which may lead to loss of interstitial cells of Cajal (ICC) and other cell types. Aims: We established mouse models of chronic caloric deficit and associated dysmotilities and studied the fate of ICC and enteric neurons in relation to local production of IGF-I. Methods: Female BALB/c mice (n=6/group) were maintained on different feeding regimens for 140 days: ad-libitum feeding (AL); limited feeding (LF) to prevent natural weight gain (˜80% of AL intake); intermittent feeding (IF): no food on odd days and AL feeding every other day. Gastric emptying of solids was monitored by 13C-octanoic acid breath test. Electrical slow wave activity was studied by intracellular technique. Density of Kit+ ICC in gastric whole-mounts was determined by confocal microscopy and multithreshold volume rendering. Myenteric neurons were enumerated by counting HuC/D+ perikarya in ganglia outlined by PGP 9.5 immunostaining. Expression of PGP 9.5 and IGF-I mRNA were studied by qRT-PCR. Results: LF mice had significantly lower body weight than AL mice, whereas weights of IF mice did not significantly differ from the AL group. IGF-I expression was decreased in both LF and IF mice relative to AL controls (P=0.004). LF and IF mice more frequently had delayed gastric emptying than AL mice (P<0.001). Slow waves were accelerated in LF mice and irregular in IF mice. In the LF group, both ICC volumes and neuron counts/ganglion were significantly reduced (P<0.001). PGP 9.5 mRNA was decreased in both LF and IF mice (P=0.015). Conclusion: Gastric dysmotility in calorically restricted mice is associated with depletion of ICC and enteric neurons. The effects of reduced food intake may in part be mediated by reduced local production of IGF-I. Grant support: NIH DK58185, DK68055 and the Rosztoczy Foundation.